Without being bound to theory, it is believed that the pathology of Alzheimer's disease (“AD”) involves amyloid-β (“Aβ”) peptides, which are metabolites of β-amyloid precursor protein (Alzheimer's disease-associated precursor protein or “APP”), and are believed to be major pathological determinants of AD. These peptides consist mainly of 40 to 42 amino acids, Aβ1-40 (“Aβ40”) and Aβ1-42 (“Aβ42”), respectively. Aβ40 and Aβ42 are generated by two enzymatic cleavages occurring close to the C-terminus of APP. The enzymes responsible for the cleavage, β-secretase and γ-secretase, generate the N- and C-termini of Aβ, respectively. The amino terminus of Aβ is formed by β-secretase cleavage between methionine residue 596 and aspartate residue 597 of APP (numbering based o APP 695 isoform). γ-secretase cleaves at varying positions 38-, 40- or 43-residues C-terminal of this β-secretase cleavage product to release the Aβ peptides. A third enzyme, α-secretase, cleaves the precursor protein between the Aβ- and γ-cleavage sites, thus precluding Aβ production and releasing an approximately 3 kDa peptide known as P3, which is non-pathological. Both β- and α-secretase cleavage also result in soluble, secreted-terminal fragments of APP, known as sAPPβ and sAPPα, respectively. The sAPPα fragment has been suggested to be neuroprotective. These secretases may also be involved in the processing of other important proteins. For example, γ-secretase also cleaves Notch-1 protein.
A drug which selectively inhibits Aβ formation and/or accumulation is thus of potential interest for the treatment, management and prevention of Alzheimer's disease. To maximize utility, however, it is also desirable that it can be readily delivered to relevant site of action in the brain. Brain is protected from chemical insult by a selective barrier, referred to as the blood-brain barrier (“BBB”), that many drug-like compounds are unable to penetrate.
International Patent Publication No. WO 03/057165 discloses that certain previously known inhibitors of tyrosine kinases are useful to inhibit the production of and accumulation of Aβ. Such compounds included those described in U.S. Pat. No. 5,521,184, which includes imatinib. Netzer et al., Proc Natl Acad. Sci., 100(21):12444-9 (2003) showed that imatinib inhibits production of Aβ without affecting γ-secretase cleavage of Notch-1 and without unacceptable toxicity to the neurons. A major disadvantage with using imatinib for the treatment or prevention of Alzheimer's disease, however, is that penetration of this compound across the BBB is poor because imatinib is actively pumped out of the brain by a P-glycoprotein system, thereby preventing high concentrations of the compound from accumulating in the brain. Accordingly, imatinib is generally not used for the treatment of cancers of the central nervous system.
International Patent Publication No. WO 05/072826 describes compositions and methods of use for tyrosine kinase inhibitors to treat pathogenic infection. J. Zimmermann et al., Bioorganic & Medicinal Chem. Lett., 7(2):187-192 describes potent and selective inhibitors of the ABL-kinase: phenylamino-pyrimidine (PAP) derivatives. International Patent Publication No. EP 1 533 304 describes amide derivatives. International Patent Publication No. WO 04/005281 describes inhibitors of tyrosine kinases. International Patent Publication No. WO 05/039586 describes the use of pyridinyl-pyrimidinylamino-benzamide derivatives for the treatment of amyloid related disorders. U.S. Pat. No. 5,521,184 describes pyrimidine derivatives and processes for the preparation thereof. International Patent Publication WO 04/110452 describes substituted phenyl compounds.